DOI QR코드

DOI QR Code

The Memory-Enhancing Effects of Liquiritigenin by Activation of NMDA Receptors and the CREB Signaling Pathway in Mice

  • Ko, Yong-Hyun (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Kwon, Seung-Hwan (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Hwang, Ji-Young (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Kim, Kyung-In (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Seo, Jee-Yeon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Nguyen, Thi-Lien (Department of Pharmacology, National Institute of Drug Quality Control) ;
  • Lee, Seok-Yong (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Kim, Hyoung-Chun (Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University) ;
  • Jang, Choon-Gon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University)
  • Received : 2016.12.27
  • Accepted : 2017.03.08
  • Published : 2018.03.01

Abstract

Liquiritigenin (LQ) is a flavonoid that can be isolated from Glycyrrhiza radix. It is frequently used as a tranditional oriental medicine herbal treatment for swelling and injury and for detoxification. However, the effects of LQ on cognitive function have not been fully explored. In this study, we evaluated the memory-enhancing effects of LQ and the underlying mechanisms with a focus on the N-methyl-D-aspartic acid receptor (NMDAR) in mice. Learning and memory ability were evaluated with the Y-maze and passive avoidance tests following administration of LQ. In addition, the expression of NMDAR subunits 1, 2A, and 2B; postsynaptic density-95 (PSD-95); phosphorylation of $Ca^{2+}$/calmodulin-dependent protein kinase II (CaMKII); phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2); and phosphorylation of cAMP response element binding (CREB) proteins were examined by Western blot. In vivo, we found that treatment with LQ significantly improved memory performance in both behavioral tests. In vitro, LQ significantly increased NMDARs in the hippocampus. Furthermore, LQ significantly increased PSD-95 expression as well as CaMKII, ERK, and CREB phosphorylation in the hippocampus. Taken together, our results suggest that LQ has cognition enhancing activities and that these effects are mediated, in part, by activation of the NMDAR and CREB signaling pathways.

Keywords

References

  1. Aamodt, S. M. and Constantine-Paton, M. (1999) The role of neural activity in synaptic development and its implications for adult brain function. Adv. Neurol. 79, 133-144.
  2. Alberini, C. M. (2009) Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev. 89, 121-145. https://doi.org/10.1152/physrev.00017.2008
  3. Armano, S., Rossi, P., Taglietti, V. and D'Angelo, E. (2000) Long-term potentiation of intrinsic excitability at the mossy fiber-granule cell synapse of rat cerebellum. J. Neurosci. 20, 5208-5216. https://doi.org/10.1523/JNEUROSCI.20-14-05208.2000
  4. Barki-Harrington, L., Elkobi, A., Tzabary, T. and Rosenblum, K. (2009) Tyrosine phosphorylation of the 2B subunit of the NMDA receptor is necessary for taste memory formation. J. Neurosci. 29, 9219-9226.
  5. Danysz, W. and Parsons, C. G. (2012) Alzheimer's disease, ${\beta}$-amyloid, glutamate, NMDA receptors and memantine-searching for the connections. Br. J. Pharmacol. 167, 324-352. https://doi.org/10.1111/j.1476-5381.2012.02057.x
  6. Easton, A.C., Lucchesi, W., Mizuno, K., Fernandes, C., Schumann, G., Giese, K. P. and Muller, C. P. (2013) ${\alpha}CaMKII$ autophosphorylation controls the establishment of alcohol-induced conditioned place preference in mice. Behav. Brain Res. 252, 72-76.
  7. Fleischmann, A., Hvalby, O., Jensen, V., Strekalova, T., Zacher, C., Layer, L. E., Kvello, A., Reschke, M., Spanagel, R., Sprengel, R., Wagner, E. F. and Gass, P. (2003) Impaired long-term memory and NR2A-type NMDA receptor-dependent synaptic plasticity in mice lacking c-Fos in the CNS. J. Neurosci. 23, 9116-9122.
  8. Goodfellow, M. J., Abdulla, K. A. and Lindquist, D. H. (2016) Neonatal Ethanol Exposure impairs trace fear conditioning and alters NMDA receptor subunit expression in adult male and female rats. Alcohol Clin. Exp. Res. 40, 309-318. https://doi.org/10.1111/acer.12958
  9. Gong, Y. and Lippa, C. F. (2010) Review: disruption of the postsynaptic density in Alzheimer's disease and other neurodegenerative dementias. Am. J. Alzheimers Dis. Other Demen. 25, 547-555.
  10. Griffith, T. N., Varela-Nallar, L., Dinamarca, M. C. and Inestrosa, N. C. (2010) Neurobiological effects of Hyperforin and its potential in Alzheimer's disease therapy. Curr. Med. Chem. 17, 391-406. https://doi.org/10.2174/092986710790226156
  11. Jensen, C., Forlini, C., Partridge, B. and Hall, W. (2016) Australian university students' coping strategies and use of pharmaceutical stimulants as cognitive enhancers. Front. Psychol. 7, 277.
  12. Kang, H. E., Jung, H. Y., Cho, Y. K., Kim, S. H., Sohn, S. I., Baek, S. R. and Lee, M. G. (2009) Pharmacokinetics of liquiritigenin in mice, rats, rabbits, and dogs, and animal scale-up. J. Pharm. Sci. 98, 4327-4342. https://doi.org/10.1002/jps.21702
  13. Kim, H. G. and Oh, M. S. (2013) Memory-enhancing effect of Mori Fructus via induction of nerve growth factor. Br. J. Nutr. 110, 86-94. https://doi.org/10.1017/S0007114512004710
  14. Kumar, N. S. and Nisha, N. (2014) Phytomedicines as potential inhibitors of beta amyloid aggregation: significance to Alzheimer's disease. Chin. J. Nat. Med. 12, 801-818.
  15. Kwon, S. H., Hong, S. I., Ma, S. X., Lee, S. Y. and Jang, C. G. (2015) 3',4',7-Trihydroxyflavone prevents apoptotic cell death in neuronal cells from hydrogen peroxide-induced oxidative stress. Food Chem. Toxicol. 80, 41-51. https://doi.org/10.1016/j.fct.2015.02.014
  16. Kwon, S. H., Ma, S. X., Joo, H. J., Lee, S. Y. and Jang, C. G. (2013) Inhibitory effects of Eucommia ulmoides Oliv. Bark on scopolamine-induced learning and memory deficits in mice. Biomol. Ther. (Seoul) 21, 462-469. https://doi.org/10.4062/biomolther.2013.074
  17. Lai, Q., Hu, P., Li, Q., Li, X., Yuan, R., Tang, X., Wang, W., Li, X., Fan, H. and Yin, X. (2016) NMDA receptors promote neurogenesis in the neonatal rat subventricular zone following hypoxicischemic injury. Mol. Med. Rep. 13, 206-212. https://doi.org/10.3892/mmr.2015.4501
  18. Lamsa, K., Irvine, E. E., Giese, K. P. and Kullmann, D. M. (2007) NMDA receptor-dependent long-term potentiation in mouse hippocampal interneurons shows a unique dependence on Ca(2+)/calmodulin-dependent kinases. J. Physiol. 584, 885-894. https://doi.org/10.1113/jphysiol.2007.137380
  19. Lee, E., Choi, S. Y., Yang, J. H. and Lee, Y. J. (2016) Preventive effects of imperatorin on perfluorohexanesulfonate-induced neuronal apoptosis via inhibition of intracellular calcium-mediated ERK pathway. Korean J. Physiol. Pharmacol. 20, 399-406.
  20. Lewis, R. J. and Garcia, M. L. (2003) Therapeutic potential of venom peptides. Nat. Rev. Drug Discov. 2, 790-802. https://doi.org/10.1038/nrd1197
  21. Liu, R. T., Tang, J. T., Zou, L. B., Fu, J. Y. and Lu, Q. J. (2011) Liquiritigenin attenuates the learning and memory deficits in an amyloid protein precursor transgenic mouse model and the underlying mechanisms. Eur. J. Pharmacol. 669, 76-83. https://doi.org/10.1016/j.ejphar.2011.07.051
  22. Liu, R. T., Zou, L. B., Fu, J. Y. and Lu, Q. J. (2010) Effects of liquiritigenin treatment on the learning and memory deficits induced by amyloid beta-peptide (25-35) in rats. Behav. Brain Res. 210, 24-31. https://doi.org/10.1016/j.bbr.2010.01.041
  23. Liu, R. T., Zou, L. B. and Lu, Q. J. (2009) Liquiritigenin inhibits $A{\beta}_{25-35}$-induced neurotoxicity and secretion of $A{\beta}_{1-40}$ in rat hippocampal neurons. Acta Pharmacol. Sin. 30, 899-906. https://doi.org/10.1038/aps.2009.74
  24. Morris, R. G., Anderson, E., Lynch, G. S. and Baudry, M. (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319, 774-776. https://doi.org/10.1038/319774a0
  25. Nakazawa, K., McHugh, T. J., Wilson, M. A. and Tonegawa, S. (2004) NMDA receptors, place cells and hippocampal spatial memory. Nat. Rev. Neurosci. 5, 361-372. https://doi.org/10.1038/nrn1385
  26. Ortega-Martinez, S. (2015) A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Front. Mol. Neurosci. 8, 46.
  27. Oskouei, D. S., Rikhtegar, R., Hashemilar, M., Sadeghi-Bazargani, H., Sharifi-Bonab, M., Sadeghi-Hokmabadi, E., Zarrintan, S. and Sharifipour, E. (2013) The effect of Ginkgo biloba on functional outcome of patients with acute ischemic stroke: a double-blind, placebo-controlled, randomized clinical trial. J. Stroke Cerebrovasc. Dis. 22, e557-e563. https://doi.org/10.1016/j.jstrokecerebrovasdis.2013.06.010
  28. Paoletti, P., Bellone, C. and Zhou, Q. (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 14, 383-400. https://doi.org/10.1038/nrn3504
  29. Qin, R. A., Yao, X. X. and Huang, Z. Y. (2012) Effects of compound danshen tablets on spatial cognition and expression of brain beta-amyloid precursor protein in a rat model of Alzheimer's disease. J. Tradit. Chin. Med. 32, 63-66. https://doi.org/10.1016/S0254-6272(12)60033-8
  30. Rajendran, P. R., Thompson, R. E. and Reich, S. G. (2001) The use of alternative therapies by patients with Parkinson's disease. Neurology 57, 790-794. https://doi.org/10.1212/WNL.57.5.790
  31. Rao, V. R. and Finkbeiner, S. (2007) NMDA and AMPA receptors: old channels, new tricks. Trends Neurosci. 30, 284-291. https://doi.org/10.1016/j.tins.2007.03.012
  32. Ruscheweyh, R., Wilder-Smith, O., Drdla, R., Liu, X. G. and SandKuhler, J. (2011) Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Mol. Pain 7, 20.
  33. Shimizu, E., Tang, Y. P., Rampon, C. and Tsien, J. Z. (2000) NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science 290, 1170-1174.
  34. Song, J. C., Seo, M. K., Park, S. W., Lee, J. G. and Kim, Y. H. (2016) Differential effects of olanzapine and haloperidol on mk-801-induced memory impairment in mice. Clin. Psychopharmacol. Neurosci. 14, 279-285. https://doi.org/10.9758/cpn.2016.14.3.279
  35. Stan, T. L., Sousa, V. C., Zhang, X., Ono, M. and Svenningsson, P. (2015) Lurasidone and fluoxetine reduce novelty-induced hypophagia and NMDA receptor subunit and PSD-95 expression in mouse brain. Eur. Neuropsychopharmacol. 25, 1714-1722. https://doi.org/10.1016/j.euroneuro.2015.07.007
  36. Stranahan, A. M. and Mattson, M. P. (2010) Selective vulnerability of neurons in layer II of the entorhinal cortex during aging and Alzheimer's disease. Neural Plast. 2010, 108190.
  37. Tang, M., Wang, Z., Zhou, Y., Xu, W., Li, S., Wang, L., Wei, D. and Qiao, Z. (2013) A novel drug candidate for Alzheimer's disease treatment: gx-50 derived from Zanthoxylum bungeanum. J. Alzheimers Dis. 34, 203-213.
  38. Vaynman, S., Ying, Z. and Gomez-Pinilla, F. (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur. J. Neurosci. 20, 2580-2590. https://doi.org/10.1111/j.1460-9568.2004.03720.x
  39. Veroniki, A. A., Straus, S. E., Ashoor, H. M., Hamid, J. S., Hemmelgarn, B. R., Holroyd-Leduc, J., Majumdar, S. R., McAuley, G. and Tricco, A. C. (2016) Comparative safety and effectiveness of cognitive enhancers for Alzheimer's dementia: protocol for a systematic review and individual patient data network meta-analysis. BMJ Open 6, e010251. https://doi.org/10.1136/bmjopen-2015-010251
  40. Wei, F., Wang, G. D., Zhang, C., Shokat, K. M., Wang, H., Tsien, J. Z., Liauw, J. and Zhuo, M. (2006) Forebrain overexpression of CaMKII abolishes cingulate long term depression and reduces mechanical allodynia and thermal hyperalgesia. Mol. Pain 2, 21.
  41. Xu, M., Chandler, L. J. and Woodward, J. J. (2008) Ethanol inhibition of recombinant NMDA receptors is not altered by coexpression of CaMKII-alpha or CaMKII-beta. Alcohol 42, 425-432. https://doi.org/10.1016/j.alcohol.2008.04.007
  42. Yamada, K., Shimizu, M., Kawabe, K. and Ichitani, Y. (2015) Hippocampal AP5 treatment impairs both spatial working and reference memory in radial maze performance in rats. Eur. J. Pharmacol. 758, 137-141. https://doi.org/10.1016/j.ejphar.2015.03.080
  43. Zhao, B., Wang, Y., Li, Y., Qiao, X., Yan, P., Zhu, Y. and Lai, J. (2015) Differential phosphorylation of NMDAR1-CaMKII-MAPKs in the rat nucleus accumbens following chronic ethanol exposure. Neurosci. Lett. 597, 60-65. https://doi.org/10.1016/j.neulet.2015.03.061

Cited by

  1. Phytochemical and Pharmacological Role of Liquiritigenin and Isoliquiritigenin From Radix Glycyrrhizae in Human Health and Disease Models vol.10, pp.1663-4365, 2018, https://doi.org/10.3389/fnagi.2018.00348
  2. Investigating the effect of Crataegus pinnatifida, a functional food, on cognition and memory deficit vol.26, pp.2, 2018, https://doi.org/10.11002/kjfp.2019.26.2.238
  3. 7,8,4'-Trihydroxyisoflavone, a Metabolized Product of Daidzein, Attenuates 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells vol.27, pp.4, 2019, https://doi.org/10.4062/biomolther.2018.211
  4. Glycyrrhizae Radix et Rhizoma Processed by Sulfur Fumigation Damaged the Chemical Profile Accompanied by Immunosuppression and Liver Injury vol.2020, pp.None, 2018, https://doi.org/10.1155/2020/5439853
  5. GluN2A/ERK/CREB Signaling Pathway Involved in Electroacupuncture Regulating Hypothalamic-Pituitary-Adrenal Axis Hyperactivity vol.15, pp.None, 2018, https://doi.org/10.3389/fnins.2021.703044
  6. ERK/MAPK signalling in the developing brain: Perturbations and consequences vol.131, pp.None, 2018, https://doi.org/10.1016/j.neubiorev.2021.10.009